This invention relates to methods for treating or preventing intestinal motility disorders, depression, prostate disease and dyslipidemia by administering a .beta..sub.3 -adrenoceptor antagonist or agonist. This invention also relates to pharmaceutical compositions for treating or preventing intestinal motility disorders, depression, prostate disease and dyslipidemia comprising a .beta..sub.3 -adrenoceptor antagonist or agonist.
.beta.-Adrenergic receptors have been categorized into .beta..sub.1, .beta..sub.2 and .beta..sub.3 -subtypes. Agonists of .beta.-receptors promote the activation of adenylyl cyclase. Activation of .beta..sub.1 -receptors invokes increases in heart rate while activation of .beta..sub.2 -receptors induces relaxation of skeletal muscle tissue which produces a drop in blood pressure and the onset of smooth muscle tremors. Activation of .beta..sub.3 -receptors is known to stimulate lipolysis (the breakdown of adipose tissue triglycerides to glycerol and free fatty acids), and thereby promote the loss of fat mass. Compounds that stimulate .beta..sub.3 -receptors are therefore useful as anti-obesity agents. In addition, compounds which are .beta..sub.3 -adrenoceptor agonists have hypoglycemic or anti-diabetic activity, but the mechanism of this effect is unknown.
Until recently .beta..sub.3 -adrenoceptors were thought to be found predominately in adipose tissue. .beta..sub.3 -receptors are now known to be located in such diverse tissues as the intestine and the brain. J. Clin. Invest., 91, 344 (1993). Stimulation of the .beta..sub.3 -receptor has been demonstrated to cause relaxation of smooth muscle in colon and trachea. Life Sciences, 44, 19, 1411 (1989); Br. J. Pharm., 112, 55 (1994). For example, stimulation of .beta..sub.3 -receptors has been found to induce relaxation of histamine-contracted guinea pig ileum, J. Pharm. Exp. Ther., 260, 1, 192 (1992).
It has now been found that there is expression of the .beta..sub.3 -receptor in human prostate. Antagonism or agonism of these receptors should result in relaxation of prostate smooth muscle and that .beta..sub.3 -agonists and antagonists should be useful for the treatment or prevention of prostate disease.
Administration of N-[(2S)-7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-hydroxy- 2-(3-chlorophenyl)-ethanamine hydrochloride, a .beta..sub.3 -agonist, has been reported to demonstrate activity in rodent models of depression, Europ. J. Pharm., 219, 193 (1992).
N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophen yl)ethanamine reduces plasma triglycerides and fatty acids in genetic animal models of obesity and diabetes and therefore will be useful for the treatment and prevention of dyslipidemia.
U.S. patent application Ser. No. 08/076,026, filed Jun. 14, 1993, discloses the use of compounds of the formula I, described below, for the treatment or prevention of diabetes, hypoglycemia, and weight loss.
U.S. Pat. No. 4,338,333, issued Jul. 6, 1982, refers to ethanamine derivatives including the compound of formula K, described below, which possess antiobesity and antihyperglycaemic activity.
U.S. Pat. No. 5,061,727, issued Oct. 29, 1991, refers to substituted 5-(2-(2-aryl-2-hydroxyethyl)-amino)-propyl)-1,3-benzodioxoles including the compound of formula J, described below, which possess antidiabetic, antihyperglycemic and antiobesity properties.
European Patent publication 516,349, published Dec. 2, 1992, refers to 2-hydroxyphenethyl amines including the compound of formula L, described below, which possess antiobesity, hypoglycemic and related utilities.